Diseases have plagued animals, including humans, for centuries. Modern medicine has successfully developed vaccines for some diseases, for example polio, thereby providing protection against infection by some disease causing pathogens. Such vaccines have improved human health and potentially save millions of lives annually. However, developing vaccines to protect against infection by some pathogens has proven to be challenging and remains elusive. For example, malaria vaccines against Plasmodium species and different strains thereof are yet to be successful.
Early attempts to develop a malaria vaccine include irradiated sporozoites that are live, but inactived or attenuated, (i.e. are capable of infecting, but not replicating in a host), Clyde 1975, Am J Trop Med Hyg 24 397. Delivery of this type of vaccine commonly relied on the attenuated live sporozoites being inoculated through mosquito bites, see Herrington et al, 1990, Bull World Health Organ. 68 Suppl 33. This type of vaccine is difficult to implement and has not resulted in a successful malaria vaccine.
Recently, a common approach in developing a vaccine is identification of a pathogen antigen, cloning of the nucleic acid encoding the antigen and protein expression of recombinant nucleic acid. This approach for developing a malaria vaccine has resulted in a number of blood-stage derived recombinant antigens for inclusion in subunit vaccines, including MSP1, MSP2, MSP3, MSP4, MSP5, AMA1, PfEMP1, RESA, RAP1, and RAP2 (Carvalhuo et al, 2002, Scand J. Immol 56 327). However, a subunit vaccine for malaria is yet to be successful.
Although subunit vaccines are the most common form of a malaria vaccine currently in development, a subunit vaccine has a number of limitations, in particular in relation to developing a vaccine against a pathogen characterised by multiple strains, for example Plasmodium. An important inadequacy of subunit vaccines is their aim to mimic natural immunity, a process that in itself may be entirely inadequate. This is illustrated, for example, from a study conducted in Kenya (Hoffman et al, 1987, Science 237 639). The researchers treated adult Kenyan volunteers who had lived their entire lives in a malaria endemic area with anti-malaria drugs and then monitored each volunteer for appearance of Plasmodium parasites in their blood over the ensuing three months. By three months, 80% of the volunteers had become infected with Plasmodium parasites although antibody levels against the pathogen circumsporozoite protein were indistinguishable between individuals who developed parasitemia and those who did not. Thus, immunity to sporozoites (the form of the parasite inoculated by the mosquito) was inadequate, immunity to liver stage parasites (the next stage in the life cycle) was inadequate and immunity to blood forms (the stage of exponential growth after the liver stage) was also inadequate.
Subunit vaccines that aim to mimic natural immune responses by inducing antibodies to the sporozoite coat, by inducing T cells which secrete INF-γ (gamma interferon) and which are potentially cytolytic for infected liver cells or inducing antibodies to merozoite surface proteins to block the invasion of red blood cells have not provided protection against malaria. There are three main possibilities why naturally occurring immune responses induced by subunits are not protective: (i) small molecules lack sufficient immunological determinants (or epitopes) to be widely immunogenic; (ii) many malaria proteins, and all major vaccine candidates, are polymorphic and these polymorphisms can be discriminated by antibodies or T cells raised against any one particular polymorphism; and (iii) malaria infection suppresses the induction of immunity by blocking dendritic cell maturation (Urban et al, 1999, Nature 400 73) and killing parasite-specific T cells by apoptosis (Xu et al, 2002, J Exp Med 195 881) and thus prevents the development of antibody-independent immunity as well as T cell-dependent antibody responses and subsequent memory responses.
It was recently shown that it was possible to immunize humans against a single strain of Plasmodium using an ultra-low dose of live P. faiciparum infected red blood cells (Pombo et al, 2002, Lancet 360 610). In this study, naive volunteers were repeatedly infected with parasites and drug treated to stop the infection. They did not develop any symptoms of malaria during the eight days during which parasite numbers increased as determined by a very sensitive Polymerase Chain Reaction (PCR). Parasites could not be detected by microscopy. Although immunisation with ultra-low dosages of live parasite may provide some protection against subsequent infection by the same parasite, it is difficult to cultivate large numbers of live parasite for use in a vaccine. Transport of live parasites to areas requiring administration of the vaccine, maintaining the parasites viability and a requirement for blood products to propagate live parasite for the vaccine is not practical and is prohibitive for general application. Areas affected by malaria are typically remote with limited facilities. Also, inoculation with live pathogen is cumbersome and requires repeated infection/treatment cycles to prevent full infection.
Rhee etal, 2002, J Exper Med 195 1565 describes vaccination of mice with heat killed Leishmania major and either IL-12 or CpG oligonucleotide (CpG-ODN). This publication relates to a specific pathogen, Leishmania major, which is the causative agent of cutaneous leishmaniasis and a vaccine for the same pathogen.
There is a need for a pharmaceutical composition capable of stimulating an immune response in an animal and reducing a risk of infection or improving recovery from an infection by one or more pathogen, namely Plasmodium spp or strain.